Pathology and current treatment of neurodegenerative sphingolipidoses.

Sphingolipidoses constitute a large subgroup of lysosomal storage disorders (LSDs). Many of them are associated with a progressive neurodegeneration. As is the case for LSDs in general, most sphingolipidoses are caused by deficiencies in lysosomal hydrolases. However, accumulation of sphingolipids can also result from deficiencies in proteins involved in the transport or posttranslational modification of lysosomal enzymes, transport of lipids, or lysosomal membrane proteins required for transport of lysosomal degradation end products. The accumulation of sphingolipids in the lysosome together with secondary changes in the concentration and localization of other lipids may cause trafficking defects of membrane lipids and proteins, affect calcium homeostasis, induce the unfolded protein response, activate apoptotic cascades, and affect various signal transduction pathways. To what extent, however, these changes contribute to the pathogenesis of the diseases is not fully understood. Currently, there is no cure for sphingolipidoses. Therapies like enzyme replacement, pharmacological chaperone, and substrate reduction therapy, which have been shown to be efficient in non-neuronopathic LSDs, are currently evaluated in clinical trials of neuronopathic sphingolipidoses. In the future, neural stem cell therapy and gene therapy may become an option for these disorders.